The roles of pleckstrin-2 as a functional node in erythropoiesis

pleckstrin-2 作为红细胞生成功能节点的作用

基本信息

批准号：
9052762
负责人：
Peng Ji
金额：
$ 36.09万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-10 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9052762
关键词：
1-Phosphatidylinositol 3-Kinase Actins Affect Anemia Apoptosis Binding Binding Proteins Biological Assay Cell Death Cell Differentiation process Cell surface Cells Cellular Structures Congenital dyserythropoietic anemia Cytoskeleton Data Data Reporting Defect Development Disease Disease Management Disease model Dysmyelopoietic Syndromes Elderly Erythroblasts Erythrocytes Erythroid Erythroid Cells Erythropoiesis Erythropoietin Etiology Exhibits Fanconi&apos s Anemia Feedback Fetal Liver Functional disorder Goals Guanosine Triphosphate Phosphohydrolases Health Hemolysis In Vitro Knockout Mice Link Lipid Binding Macrocytic Anemia Mediating Mitochondria Modification Mus Oxidative Stress PI3 gene Pathogenesis Pathway interactions Play Post-Translational Protein Processing Proteins Publishing Regulation Reporting Research Role Series Sideroblastic Anemia Signal Pathway Signal Transduction Staging Stress System Testing Therapeutic Transcriptional Regulation Translational Regulation Transplantation Work beta Thalassemia cofilin cofilin 2 fetal in vitro testing in vivo insight knock-down leukemia mouse model novel novel therapeutics phospholipase D1 platelet protein P47 prevent receptor

项目摘要

DESCRIPTION (provided by applicant): Research in the past few decades has revealed many key factors in erythropoietin (Epo) and Rac GTPase signaling pathways that are important for the development of various red blood cell related diseases. However, the pathogenesis of many other erythroid disorders, such as congenital dyserythropoietic anemias, Fanconi anemia, sideroblastic anemia, unexplained anemia of the elderly, ineffective erythropoiesis in beta-thalassemia, and myelodysplastic syndromes, remain unclear. These diseases often show unexplained defects in cell differentiation, survival, and actin dynamics that mimic disruptions of Epo and/or Rac GTPase pathways. However, no direct defects in Epo or Rac GTPase pathways have been reported to date in these diseases. An open question in the field is whether there are any proteins or pathways that link Epo and Rac GTPase pathways to regulate terminal erythropoiesis, which could be involved in the pathogenesis of aforementioned diseases. In this effort, we discovered that pleckstrin-2 (plek2) plays a critical role in different stages of terminl erythropoiesis through the interaction with cofilin. Our preliminary data and reports from other groups indicated that plek2 is closely interrelated with Epo and Rac GTPase pathways to regulate erythroid cell differentiation, survival and actin dynamics to form a global regulatory network in erythropoiesis. In this project, we will determine the roles of plek2 as a functional node in erythropoiesis in vitro and in vivo using our well-established mouse fetal erythroblast culture system and various mouse models. In Aim 1, we will use plek2 knockout mouse model, which showed macrocytic anemia and fetal anemia, to determine the functions of plek2 in erythropoiesis in vivo under steady state and stress conditions. The role of plek2 in the pathogenesis of beta-thalassemia will also be tested using Hbbth1/th1 mice as a direct red cell disease model for plek2. In Aim 2, we will determine the mechanisms by which plek2 is regulated by Epo signaling pathways transcriptionally or through post-translational modifications. In Aim 3, we will determine the extent to which plek2-cofilin and Rac GTPase pathways are reciprocally required in different stages of terminal erythropoiesis. Successful accomplishment of these independent but interconnected aims will reveal a central role of plek2 in regulating cell differentiation, survival and actin dynamics in erythropoiesis, which could provide novel insights into the pathogenesis and therapeutic management of red cell related diseases with unclear etiology.

描述（由适用提供）：在过去的几十年中，研究揭示了促红细胞生成素（EPO）和RAC GTPase信号通路的许多关键因素，这些因素对于各种红细胞相关疾病的发展很重要。然而，许多其他红细胞性疾病的发病机理，例如先天性dyserythropoietic贫血，fanconi贫血，Sideroblastic贫血，无法解释的老年人的贫血，无效的erythropoiesis beta- thalsasmia和Merelodsplastic Syndrosplastic综合征，无效。这些疾病通常在细胞分化，生存和肌动蛋白动力学中表现出无法解释的缺陷，这些缺陷模仿了破坏 EPO和/或RAC GTPase途径。但是，在这些疾病中，尚无据报道EPO或RAC GTPase途径的直接缺陷。该领域的一个空旷的问题是，是否有任何蛋白质或途径将EPO和RAC GTPase途径连接起来调节末端红细胞生成，这可能与合理疾病的发病机理有关。在这项工作中，我们发现Pleckstrin-2（Plek2）通过与Cofilin的相互作用在末端红细胞生成的不同阶段起关键作用。我们的初步数据和其他小组的报告表明，PLEK2与EPO和RAC GTPase途径密切相关，以调节红细胞分化，生存和肌动蛋白动态，以形成红细胞生成的全球调节网络。在这个项目中，我们将使用我们建立的小鼠胎儿胎儿红细胞培养系统和各种小鼠模型来确定PLEK2作为促红细胞生成和体内功能性节点的作用。在AIM 1中，我们将使用PLEK2基因敲除小鼠模型，该模型显示出大细胞性贫血和胎儿贫血，以确定在稳态和应力条件下，PLEK2在体内的红细胞生成中的功能。 PLEK2在β-地中海贫血的发病机理中的作用也将使用HBBTH1/TH1小鼠作为PLEK2的直接红细胞疾病模型进行测试。在AIM 2中，我们将确定AIM 3中的机制，我们将确定在末端红细胞生成的不同阶段，PLEK2-COFILIN和RAC GTPase途径在多大程度上需要相互要求。成功完成这些独立但相互联系的目标将揭示PLEK2在红细胞生成中确定细胞分化，生存和肌动蛋白动力学方面的核心作用，这可以为与不明确病因的红细胞相关疾病的发病机理和治疗性管理提供新的见解。